citalopram Celexa
Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram.

Hyttel J, Overo KF, Arnt J.

The effects in rats of long-term administration of the potent, specific 5-HT uptake inhibitor citalopram have been investigated. Citalopram hydrobromide (MW = 405) was given in the diet, 99 or 25 mumol/kg daily, for 13 days or orally, 49 mumol/kg twice a day, for 14 days. High plasma and brain levels of citalopram were found during the treatment period, whereas negligible amounts were found 24 h after withdrawal. The 5-HT uptake mechanism in blood platelets was completely blocked, since levels of whole blood 5-HT during and shortly (2 days) after treatment were decreased by 75-90%. The drug load after the two highest doses in terms of plasma drug levels was the same as in depressed patients treated with citalopram. Receptor binding technique ex vivo was applied to different brain parts to measure receptor parameters for several neurotransmitters. All data were evaluated by Eadie- Hoffstee analysis. No changes were seen in Bmax and Kd for beta-receptors (3H-dihydroalprenolol) in frontal cortex, occipital + temporal cortex, whole cortex and limbic structures, 5-HT2 receptors (3H-spiroperidol) in frontal and whole cortex, alpha 1-receptors (3H-prazosin) in "rest of brain" and DA D-2 receptors (3H-spiroperidol) in corpus striatum and limbic structures. The uptake mechanism for 5-HT as well as the inhibitory effect of citalopram on this uptake remained unaffected in brain synaptosomes derived from control and from citalopram (99 mumol/kg)-treated rats. Thus long-term treatment with citalopram does not induce changes in neurotransmitter receptors as seen with most tricyclic as well as newer " atypical " antidepressants.(ABSTRACT TRUNCATED AT 250 WORDS)

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citalopram Celexa
Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor, citalopram.

Arnt J, Overo KF, Hyttel J, Olsen R.

The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 mumol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mumol/kg for 13 days and after oral bolus injection (49 mumol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.

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citalopram Celexa
Thermoregulatory effects of the specific uptake inhibitor citalopram in maturing mice.

Goodrich C.

The effects of a single 20 mg/kg dose of citalopram (Lu 10-171) were studied in mice aged 1-10 days. Body temperature measured 2 and 24 hr after treatment was decreased in treated animals as compared with saline injected littermate controls. Two hours after treatment, temperature preference in a thermal gradient was unchanged in animals younger than 6 days; however, in animals 6 days or older, temperature preference was increased as compared with littermate controls. Twenty-four hours after treatment, temperature preference was increased in citalopram-treated animals at all ages tested. The results are discussed in relation to nervous system maturation.

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citalopram Celexa
High-performance liquid chromatographic determination of citalopram and four of its metabolites in plasma and urine samples from psychiatric patients.

Oyehaug E, Ostensen ET, Salvesen B.

A high-performance liquid chromatographic method is used for the determination of citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phthalancarbonitrile+ ++] and four of its metabolites (the methylamino, amino, propionic acid and N-oxide derivatives) in plasma and urine. The plasma samples were extracted with diethyl ether at pH 10 and pH 4. Filtered urine samples could be injected directly on to the column. Steady-state drug and metabolite levels were investigated in fifteen psychiatric patients. In urine, 12 +/- 5% (mean +/- S.D.) of a given dose of citalopram was excreted in unchanged form. The propionic acid derivative was further conjugated, possibly to glucuronic acid. Mean steady-state plasma levels and metabolites in 24-h urine are given as percentages of the dose.

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citalopram Celexa
Prolonged treatment with the specific 5-HT-uptake inhibitor citalopram: effect on dopaminergic and serotonergic functions.

Arnt J, Hyttel J, Overo KF.

The effect of prolonged administration of the clinically effective and specific serotonin (5-HT)-uptake-inhibitor, citalopram, has been studied in rats on behavioural measures of dopaminergic (DA) and serotonergic activity and on DA D-2, 5-HT2, alpha 1- and beta-adrenergic receptor number and affinity in vitro. Thirteen days treatment with citalopram in the diet (40 mg/kg/day) did not change receptor binding for either of the ligands studied, although citalopram was detected in high concentrations in brain and plasma and induced a 75% depletion of 5-HT in whole blood. This citalopram dose-regimen was followed by a potentiated hypermotility response to d-amphetamine. Also DA-dependent hypermotility induced by methylphenidate and (+)-3-PPP was increased. In contrast, the 5-HT2-receptor mediated head shake syndrome induced by 1-5-HTP or quipazine was decreased after prolonged citalopram treatment. Two weeks oral bolus treatment (10 mg/kg once or twice daily) with the 5-HT-uptake-inhibitors citalopram, fluoxetine, zimelidine, cyanimipramine or paroxetine induced d-amphetamine potentiation, whereas amitriptyline, nortriptyline, imipramine, iprindole, and mianserin treatment showed no effect. It is suggested that d-amphetamine potentiation induced by citalopram is mainly dependent on DA mechanisms, and that this profile is characteristic for preferential 5-HT-uptake-inhibitors. The lack of correlation between behavioural effect and receptor changes was important. Since citalopram has been shown to have clinical antidepressant activity, it is concluded that down-regulation of beta-adrenoceptors is not a prerequisite for antidepressant action.

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citalopram Celexa
Salivation after single-doses of the new antidepressants femoxetine, mianserin and citalopram. A cross-over study.

Clemmesen L, Jensen E, Min SK, Bolwig TG, Rafaelsen OJ.

Twelve healthy volunteers were given oral single doses of a reference drug (nortriptyline), test drugs, and placebo on a randomised single-blind basis at weekly intervals. The doses corresponded to average daily patient medication. Spontaneous whole mouth salivation was measured before (at 10 p.m.) and 10 hours after drug administration (at 8 a.m.). Drug plasma levels were determined after 4 and 10 hours. When analysing the salivations 10 hours after drug administration adjusted for the effects of the pre-treatment salivations, statistically significant inhibition of salivation was found after nortriptyline (56%), femoxetine (34%), and mianserin (29%) when compared with placebo, while for citalopram and cis- and trans-flupenthixol no significant inhibition of salivation was demonstrated (Fig. 1, Table 5). From the estimated log linear regression coefficients, relating adjusted salivation rates and drug plasma levels 10 hours after drug administration (Table 6), and reported average steady-state plasma drug levels (Table 7), semiquantitative predictions of the average level of anticholinergic activity during long-term treatment may be made: For femoxetine and mianserin, moderate anticholinergic activity, less pronounced than with nortriptyline, are predicted, while for citalopram no such activity can be predicted (Table 7).

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citalopram Celexa
CNS effects of citalopram, a new serotonin inhibitor antidepressant (a quantitative pharmaco-electroencephalography study).

Itil TM, Menon GN, Bozak MM, Itil KZ.

Citalopram, a new phthalane derivative and a specific serotonin re-uptake inhibitor in animal pharmacological tests, was evaluated in a double-blind, crossover, quantitative pharmaco-EEG (QPEEGTM) study in healthy human volunteers. The CNS effects of citalopram are linear, dose- and time-related, can statistically be differentiated from placebo, and indicate a rapid onset of effects with short duration. According to the Computer Data Bank, citalopram has a mode of action similar to mood elevators (antidepressants) with fewer sedative properties. Thus the therapeutic action of citalopram is predicted to be similar to desipramine and protriptyline from the tricyclics, and fluvoxamine from non-tricyclics. According to data bank assessment, it is hypothesized that the single antidepressant dose of citalopram is to be more than 25 mg, which should be given t.i.d. in clinical trials.

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citalopram Celexa
[Open preliminary study of new antidepressive compound: citalopram]

[Article in French]

Ropert R, Loo H, Gay C.

The antidepressant effect of citalopram, a specific inhibitor of the reuptake of serotonin, was explored in an open phase II study involving twenty-one patients hospitalized for depression. Fourteen patients responded, six did not and one was excluded from the study. These preliminary results suggest that citalopram is an effective, well tolerated antidepressant.

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